Chemoimmunotherapy by combining oxaliplatin with immune checkpoint blockades reduced tumor burden in colorectal cancer animal model

Wang, Weiwei; Wu, Ling; Zhang, Jiansheng; Wu, Huiguo; Han, En-Kun; Guo, Qiang

doi:10.1016/j.bbrc.2016.12.180

Cited by 47 publications

(31 citation statements)

References 22 publications

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“…~30% obtained with single-agent platinum doublet treatment) (NCT00527735) ( 99 ). More recently, a chemo-immunotherapy approach to murine colorectal cancer, combining oxaliplatin with PD-1 or CTLA-4 blockade proved synergistic by generating high levels of TILs and pro-inflammatory cytokines and downregulating inhibitory checkpoints ( 100 ).…”

Section: Emerging Targets and Combination Therapiesmentioning

confidence: 99%

Immuno-Oncology: Emerging Targets and Combination Therapies

2018

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Host immunity recognizes and eliminates most early tumor cells, yet immunological checkpoints, exemplified by CTLA-4, PD-1, and PD-L1, pose a significant obstacle to effective antitumor immune responses. T-lymphocyte co-inhibitory pathways influence intensity, inflammation and duration of antitumor immunity. However, tumors and their immunosuppressive microenvironments exploit them to evade immune destruction. Recent PD-1 checkpoint inhibitors yielded unprecedented efficacies and durable responses across advanced-stage melanoma, showcasing potential to replace conventional radiotherapy regimens. Neverthless, many clinical problems remain in terms of efficacy, patient-to-patient variability, and undesirable outcomes and side effects. In this review, we evaluate recent advances in the immuno-oncology field and discuss ways forward. First, we give an overview of current immunotherapy modalities, involving mainy single agents, including inhibitor monoclonal antibodies (mAbs) targeting T-cell checkpoints of PD-1 and CTLA-4. However, neoantigen recognition alone cannot eliminate tumors effectively in vivo given their inherent complex micro-environment, heterogeneous nature and stemness. Then, based mainly upon CTLA-4 and PD-1 checkpoint inhibitors as a “backbone,” we cover a range of emerging (“second-generation”) therapies incorporating other immunotherapies or non-immune based strategies in synergistic combination. These include targeted therapies such as tyrosine kinase inhibitors, co-stimulatory mAbs, bifunctional agents, epigenetic modulators (such as inhibitors of histone deacetylases or DNA methyltransferase), vaccines, adoptive-T-cell therapy, nanoparticles, oncolytic viruses, and even synthetic “gene circuits.” A number of novel immunotherapy co-targets in pre-clinical development are also introduced. The latter include metabolic components, exosomes and ion channels. We discuss in some detail of the personalization of immunotherapy essential for ultimate maximization of clinical outcomes. Finally, we outline possible future technical and conceptual developments including realistic in vitro and in vivo models and inputs from physics, engineering, and artificial intelligence. We conclude that the breadth and quality of immunotherapeutic approaches and the types of cancers that can be treated will increase significantly in the foreseeable future.

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Section: Emerging Targets and Combination Therapiesmentioning

confidence: 99%

Immuno-Oncology: Emerging Targets and Combination Therapies

2018

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“…The VE-822 þ oxaliplatin combination promotes the antitumor T-cell response Oxaliplatin has been described to induce ICD in vitro and in vivo in different preclinical cancer models (4,24). ICD is a specific cell death characterized by the release or expression of damage-associated molecular patterns (DAMP), such as adenosine-5 0 -triphosphate (ATP) and HMGB-1 release and CRT translocation.…”

Section: The Ve-822 þ Oxaliplatin Combination Induces Apoptosis Redumentioning

confidence: 99%

Inhibition of Ataxia-Telangiectasia Mutated and RAD3-Related (ATR) Overcomes Oxaliplatin Resistance and Promotes Antitumor Immunity in Colorectal Cancer

et al. 2019

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Immune cell death IFN production Antitumoral immunity Oxaliplatin + ATRi Cell autonomous cell death Cytoplasmic DNA Proliferation inhibition Apoptosis induction DNA damage Replication stress Although many patients with colorectal cancer initially respond to the chemotherapeutic agent oxaliplatin, acquired resistance to this treatment remains a major challenge to the long-term management of this disease. To identify molecular targets of oxaliplatin resistance in colorectal cancer, we performed an shRNA-based loss-of-function genetic screen using a kinome library. We found that silencing of ataxia-telangiectasia mutated and RAD3-related (ATR), a serine/threonine protein kinase involved in the response to DNA stress, restored oxaliplatin sensitivity in a cellular model of oxaliplatin resistance. Combined application of the ATR inhibitor VE-822 and oxaliplatin resulted in strong synergistic effects in six different colorectal cancer cell lines and their oxaliplatin-resistant subclones, promoted DNA single-and double-strand break formation, growth arrest, and apoptosis. This treatment also increased replicative stress, cytoplasmic DNA, and signals related to immunogenic cell death such as calreticulin exposure and HMGB1 and ATP release. In a syngeneic colorectal cancer mouse model, combined administration of VE-822 and oxaliplatin significantly increased survival by promoting antitumor T-cell responses. Finally, a DNA repair gene signature discriminated sensitive from drug-resistant patients with colorectal cancer. Overall, our results highlight the potential of ATR inhibition combined with oxaliplatin to sensitize cells to chemotherapy as a therapeutic option for patients with colorectal cancer. Significance: These findings demonstrate that resistance to oxaliplatin in colorectal cancer cells can be overcome with inhibitors of ATR and that combined treatment with both agents exerts synergistic antitumor effects.

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“…The current primary first-line therapy for the treatment of patients with CRC is combination therapy with 5-fluorouracil (5-FU), leucovorin, and Oxaliplatin (Oxa), or FOLFOX (21). Both of the individual arms of this regimen, 5-FU and Oxa, have been shown to improve anti-tumor immunity (22)(23)(24). To develop effective combination strategies that capitalize on the benefits of both chemotherapy and immune based therapy, we sought to investigate the immune effects of this chemotherapeutic regimen in the context of CRC.…”

Section: Introductionmentioning

confidence: 99%